Cytokines: Interleukins
121
than constitutively, produced and mainly
affect the working of the immune system,
suggests they have been evolved primarily
for triggering host defense mechanisms
against infectious microorganisms. They
have been clearly shown to regulate both
cell-mediated and humoral immunity. As
such, they could also be important in
antitumor mechanisms and in chronic de-
generative diseases.
The
role(s)
of
many
interleukins
in
preventing
or
combating
infectious
or
invasive
diseases
has
been
supported
by
numerous
studies
carried
out
in
experimental animal model systems. The
antitumor effect of interleukin-2 (IL-2)
has looked, for example, to be the most
efFcacious in causing tumor regression in
allogenic and xenogenic tumors in mice.
These
studies
have
stimulated
clinical
interest in interleukins, and in recent years
many clinical trials to evaluate interleukins
as anticancer agents have been carried out.
IL-2 has been used extensively, but as with
I±N
α
, its usefulness in treating cancer has
appeared limited. It also causes severe side
effects. Less is known generally about what
clinical use other interleukins might offer;
however, some such as IL-1 look to be
too toxic. It is thus not at all certain that
the therapeutic application of individual
interleukins, which now number up to
interleukin-29
(IL-29),
will
signiFcantly
affect the outcome or the management
of clinical diseases.
2
Interleukin Proteins and Genes
2.1
Interleukin Proteins
There are now 29 distinct biologically ac-
tive mediators that have been classiFed as
interleukins (Table 1). However, the actual
number of molecularly distinct proteins
i
sl
a
r
g
e
rt
h
a
n2
9b
e
c
a
u
s
es
om
ei
n
t
e
r
-
leukins are comprised of more than one
molecular species, for example, IL-1, IL-
8, IL-17. A comparable situation exists for
thetypeIin
ter
feron(I±N
)fam
i
ly
,where
for human I±N
α
in particular, there are
12 related molecular species known as
subtypes. In the case of IL-1, initially
three structurally related proteins, two of
which are biologically active, that is IL-
1
α
and IL-1ß, and the third, which is
an inhibitor of IL-1
α
/ß actions, known
as IL-1 receptor antagonist (IL-1ra), were
identiFed. The latter is the only known
interleukin without agonistic activity and
which behaves as a competitive inhibitor
of an interleukin. More recently, seven
more structural homologs of IL-1 have
been described, including one that is more
commonly known as IL-18. Other exam-
ples of structurally related interleukins that
nevertheless are designated as differently
numbered interleukins, for example, IL-
10, IL-19, IL-20, IL-22, IL-24, and IL-26,
(IL-28, IL-29), are now known. In one or
two cases, the interleukin name has proved
less appropriate, for example, IL-8, which
is now clearly just one of a large family
of chemokines.
The interleukins exhibit a wide variety
of primary structures, sizes, and post-
translational modiFcations. At the tertiary
level, however, the interleukins generally
fall into but a few categories. Excluding
the IL-1 and IL-8 families, the major-
ity of interleukins are
α
-helical proteins,
which although unrelated in amino acid
sequences, fold up as 4-6-
α
-helix bun-
dles. This
α
-helical bundle structure is
common to IL-2, IL-3, IL-4, IL-5, IL-6, IL-
7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15,
and most of the newly described inter-
leukins
(±ig. 1).
The
structures
of
the
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